Article

Two-Step Mechanism of Membrane Disruption by Aβ through Membrane Fragmentation and Pore Formation.

Department of Chemistry, University of Michigan, Ann Arbor, Michigan.
Biophysical Journal (Impact Factor: 3.83). 08/2012; 103(4):702-10. DOI: 10.1016/j.bpj.2012.06.045
Source: PubMed

ABSTRACT Disruption of cell membranes by Aβ is believed to be one of the key components of Aβ toxicity. However, the mechanism by which this occurs is not fully understood. Here, we demonstrate that membrane disruption by Aβ occurs by a two-step process, with the initial formation of ion-selective pores followed by nonspecific fragmentation of the lipid membrane during amyloid fiber formation. Immediately after the addition of freshly dissolved Aβ(1-40), defects form on the membrane that share many of the properties of Aβ channels originally reported from single-channel electrical recording, such as cation selectivity and the ability to be blockaded by zinc. By contrast, subsequent amyloid fiber formation on the surface of the membrane fragments the membrane in a way that is not cation selective and cannot be stopped by zinc ions. Moreover, we observed that the presence of ganglioside enhances both the initial pore formation and the fiber-dependent membrane fragmentation process. Whereas pore formation by freshly dissolved Aβ(1-40) is weakly observed in the absence of gangliosides, fiber-dependent membrane fragmentation can only be observed in their presence. These results provide insights into the toxicity of Aβ and may aid in the design of specific compounds to alleviate the neurodegeneration of Alzheimer's disease.

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    • "Taken together, these data strongly suggested that the AMP properties of Ab 1-42 differed significantly from those of LL-37 and further suggested that Ab 1-42 initiated its anti-viral effects prior to HSV-1 entry into the cells. Studies using model membranes (Jang et al. 2013; Masters and Selkoe 2012; Zhao et al. 2012; Sciacca et al. 2012), human neurons and mouse fibroblasts (Jang et al. 2010) have shown that Ab peptides can insert into lipid bilayers and form toxic ion channels that destabilize cellular ionic balance. Therefore, we tested the possibility that this mechanism could explain the anti-viral activity of Ab peptides. "
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    • "This finding led us to propose that the increase in Ca 2+ permeability observed in cells exposed to Aβ results from the activity of calcium ion channels formed by Aβ in the cell surface membrane (Arispe et al. 1994a, b) (Arispe et al. 2010). While there is a growing consensus that Aβ peptides increase membrane conductance by forming conductive pores (Aguayo et al. 2009; Parodi et al. 2010; Sepulveda et al. 2010; Schauerte et al. 2010; Johnson et al. 2011; Tofoleanu and Buchete 2012; DeMuro et al. 2011; Sciacca et al. 2012; Prangkio et al. 2012; Schauerte et al. 2010; DeMuro et al. 2011), there has not been a systematic study on how a "
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    • "Indeed, oligomeric complexes of Aβ or α-syn may penetrate cell membranes, stimulating Ca 2+ influx and leading to cell death [16] [17] [18]. The mechanism of lipid bilayer disruption by aggregate species may involve insertion of distinct pore-like structures, formation of large " defects " in the membrane , or a combination of both [19] [20] [21] [22] [23] [24]. Moreover, the first study has been recently published demonstrating increased phospholipid vesicle leakage, in association with decreased cell viability, induced by tau aggregation intermediates [25]. "
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Questions & Answers about this publication

  • Jeffrey R Brender added an answer in Amyloid Beta-Peptides:
    Amyloid beta peptide (22-35), (16-22). How are these fragments biologically relevant?
    In literature interaction of Amyloid beta peptide with membrane sometimes attributed to the fragments (22-35) or (16-22). As they are the transmembrane components of the peptide. Assuming that, I am wondering about biological relevance of these fragments compare to the whole peptide (1-40, 1-42)?
    Jeffrey R Brender · University of Michigan
    If you are working with membrane disruption by Abeta you may want to look at this paper:
    https://www.researchgate.net/publication/230796871_Two-Step_Mechanism_of_Membrane_Disruption_by_A_through_Membrane_Fragmentation_and_Pore_Formation
    For general information on amyloids you want to look at this thread and join the project associated with it:
    https://www.researchgate.net/post/Amyloid_protocols_project